1. Field of the Invention
The field of the invention disclosed in this application relates to circadian rhythms in humans, and particularly to the synchronization of such human circadian rhythms with the external environment. Specifically, this invention describes methods for achieving a chronobiologic (circadian phase-shifting) effect in humans. The invention provides methods to specifically advance or delay the phase of certain circadian rhythms in humans. Specific embodiments of the invention comprise methods for alleviating the effects of transmeridional travel (i.e., jet lag); methods for alleviating circadian phase disturbance-based psychological disorders (such as winter depression or seasonal affective disorder); and methods for achieving synchrony between a human""s wake/sleep cycle or other circadian rhythms and the human""s occupational and other human activity schedules. Such re-synchrony enabled by the methods of this invention is achieved by the administration of effective amounts of melatonin at specific and predictable times based upon an individual human""s circadian rhythm phase response curve (PRC).
2. Background of the Related Art
The phenomenon of circadian rhythms in biology is well known, and circadian rhythms are exhibited by all eukaryotic plants and animals, including man. Biological rhythms are periodic fluctuations in biological properties over time; these include circadian as well as seasonal variations. Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as hormones, the regulation of body temperature, and behaviors such as wakefulness, sleep and periods of activity.
In nature, circadian rhythms are closely tied to environmental cues that impose a 24-hour pattern on many of these fluctuations. Experimental inquiry has established that when these cues are absent, most circadian rhythms have a periodicity of approximately 25 hours. Circadian rhythms that are not regulated by environmental cues are said to be free-running. The regulation of circadian rhythms by signals from the environment is said to involve entrainment of the circadian rhythm. The environmental signals that affect entrainment have been termed zeitgebers, an example of which is the light-dark cycle.
It is thought in this art that the control of circadian rhythms in mammals is mediated by a portion of the brain called the superchiasmatic nucleus (SCN). Circadian rhythms are primarily entrained by the light and dark cycle: light signals are conveyed by the retina to the SCN, and the pineal gland produces melatonin (N-acetyl-5-methoxytryptamine), which is regulated by the SCN.
Disruption of circadian rhythms can result in a number of pathophysiological states in humans; the most common of these is jet lag. The use of melatonin to ameliorate the effects of jet lag has been described in the prior art.
U.S. Pat. Nos. 4,665,086 and 4,600,723 teach the use of melatonin to alleviate the symptoms of jet lag. These patents teach the use of 1-10 mg of melatonin, taken at destination bedtime, and again upon premature awakening in the middle of the night. In view of the fact that such large dosages of melatonin are known to exert a soporific (sleep-inducing) effect, and further that external zeitgebers such as the light/dark cycle also act to re-entrain the circadian rhythm of a human""s sleep/wake cycle following transmeridional flight, it is not clear whether melatonin is capable of directly causing any change in the circadian rhythm of endogenous melatonin production when it is administered according to the teachings of these patents.
Gwinner and Benzinger, 1978, J. Comp. Physiol. 126: 123-129 teach that daily injections of melatonin can entrain the activity/rest cycle in birds.
Arendt et al., 1984, Neurosci. Lett. 45: 317-325 and Arendt et al., 1985, CIBA Found. Symp. 117: 266-283 disclose that melatonin in high doses increases tiredness and the tendency to sleep in humans.
Underwood, 1986, J. Pineal Res. 3: 187-196 discloses a PRC for melatonin in the lizard Sceloporus occidentalis. 
Arendt et al., 1987, Ergonomics 30: 1379-1393 disclose the administration of melatonin to alleviate jet lag by oral administration of exogenous melatonin 4 to 6 hours prior to the human""s normal bedtime and upon awakening in the middle of the night.
Mallo et al., 1988, Acta Endocrinol. 119: 474-480 teach that the administration of 8 mg of melatonin to humans, one hour before bedtime over a course of four days, results in a slight phase advance three days after cessation of the melatonin treatment.
Armstrong et al., 1989, Experientia 45: 932-938 disclose that in rats the effects of exogenous melatonin administration on the circadian rhythm of the sleep/wake cycle depends on the time of administration relative to the sleep/wake cycle, and that the effect was greatest when exogenous melatonin was administered a few hours before the effective start of the nocturnal activity cycle. However, these authors were unable to demonstrate phase-delay shifts or graded changes in magnitude of phase-advance shifts, nor did and they relate the timing of exogenous melatonin administration to the time of the endogenous melatonin onset.
Petrie et al., 1989, Br. Med. J. 298 705-707 teach the administration of 5 mg of melatonin to humans on a schedule of three days before flight, during flight, and once a day for three days after arrival to alleviate jet lag caused by flights from Auckland, New Zealand to London and back.
Skene et al., 1989, Sleep ""88(J. Home, ed.), pp. 39-41 teach the use of melatonin to treat jet lag.
Samel et al., 1991, J. Biol. Rhythms 6: 235-248 teach the use of melatonin for the treatment of jet lag using an administration schedule of melatonin administration at 1800 hr local time for 3 days before the time shift, and at 1400 hr local time for 4 days afterwards.
Nickelsen et al., 1991, Adv. Pineal Res. 5: 303-306 teach the administration of 5 mg melatonin at destination bedtime for the treatment of jet lag resulting from 6, 9 and 11 hour time-shifts.
Claustrat et al., 1992, Biol. Psychiatry 32: 705-711 teach the use of melatonin to affect circadian rhythms.
Entrainment and regulation of the melatonin circadian rhythms have been demonstrated in a number of animal species. The ability to effect an actual change in phase of the circadian rhythm would be useful for the alleviation of a number of circadian-rhythm related disorders.
Lewy and Sack, U.S. Pat. Ser. No. 5,242,941, issued Sept. 7, 1993 to the present inventors, was the first disclosure of a phase-response curve for melatonin in humans. This reference shows that the appropriate time to administer melatonin to induce a change in phase of a variety of human circadian rhythms is related to the time of dim light melatonin onset (DLMO). Contrary to the rather simplistic view held by the prior art (i.e., that melatonin was simply associated with darkness, which came to be thought of as being equivalent to sleep in diurnal animals), this patent disclosure established that the circadian rhythm of endogenous melatonin production was tightly coupled to the endogenous circadian pacemaker that regulates the timing of a variety of other human circadian rhythms (such as core body temperature, cortisol and sleep propensity), and that affecting the phase of the human melatonin circadian rhythm by administration of exogenous melatonin could produce both phase advances and phase delays in human circadian rhythms. A particularly novel teaching of this patent disclosure was that the magnitude and direction (i.e., phase advance or phase delay) of the desired circadian rhythm phase shift was dependent on the time of melatonin administration that resulted in the desired circadian rhythm phase-shifting effect. Again contrary to the established teachings of the prior art, this patent prescribed administration of non-soporific dosages of melatonin at times that (usually) were not equivalent to destination bedtime, based on the human melatonin phase response curve (PRC). The teachings of this patent are hereby expressly incorporated by reference.
The human melatonin PRC clearly shows that melatonin acts like darkness on the circadian rhythm of the wake/sleep cycle in humans. Sleep alone has been found to have little if any chronobiologic effect in humans; however it is possible that sleep may potentiate the phase-shifting effects of melatonin and darkness. Melatonin is produced in humans only during nighttime darkness and not during daytime darkness, suggesting that melatonin may act by helping the endogenous circadian pacemaker to discriminate between the nighttime dark period and sporadic episodes of daytime darkness (including daytime sleep). Melatonin in combination with dim light thus might be a more effective darkness zeitgeber than darkness alone in the absence of melatonin.
The human melatonin PRC described in U.S. Pat. No. 5,242,941 suggested that exogenous melatonin would be most effective when administered during the light period, to compete with light as a xe2x80x9csubstitute for darknessxe2x80x9d. The present invention is based on our further findings that the critical variable in determining the proper time for melatonin administration is the relationship between the time of melatonin administration and the DLMO time of an individual human. This finding has provided the basis for the methods of the instant invention, which methods enable treatment of a variety of circadian rhythm phase disturbances in humans by administration of exogenous melatonin at the times described hereinbelow.
This invention relates to methods for achieving a chronobiologic (phase-shifting) effect in a human. This effect is achieved by affecting a human""s circadian rhythm by administering exogenous melatonin to the human at an appropriate time relative to the human""s dim light endogenous melatonin onset time.
The circadian rhythm of melatonin production in a human is entrained principally by the (bright) light-dark cycle and reflects a variety of other biological properties which vary with a circadian rhythm. The methods of the invention entail the phase-shifting of the circadian rhythm by administration of exogenous melatonin. More specifically, the method of the invention involves the administration of a particular dosage of melatonin to the human. The present invention contemplates the administration of various doses of melatonin which promote quantitative shifts in an individual""s endogenous circadian pacemaker. The administration of sufficient doses of melatonin is capable of shifting the melatonin PRC by an appropriate degree. A linear dose effect has been found as described hereinbelow at melatonin dosages from about 0.125 mg to about 0.5 mg melatonin. Thus, in a preferred embodiment, melatonin is administered in dosages preferably from about 0.05 to 5 mg, more preferably from about 0.1 to 2 mg, and most preferably from about 0.1 to 1 mg. In a preferred embodiment, the total dose of melatonin is given in one dose.
The present invention also contemplates the use of melatonin precursors, agonists, antagonists, and compounds which mimic melatonin activity, in place of melatonin (N-acetyl-5-hydroxytryptamine) itself.
Further, the method of the invention relates to the timing of the administration of the dosage of melatonin to the human. The timing of this dosage in the human as described results in a specific phase shift in the human""s circadian rhythm of endogenous melatonin production. The method described in the invention can be used to advance or delay the phase of the circadian rhythm of melatonin production in the human. In this way, the present invention is able to alleviate circadian rhythm disorders of both the phase-delay and the phase-advance types.
The present inventors have discovered that the time of administration of exogenous melatonin relative to the time of endogenous melatonin onset is critical to the production of the appropriate phase-shifting effect. The time of exogenous melatonin administration is kept constant relative to the human""s DLMO time, which changes during a course of exogenous melatonin treatment as provided by the methods of the invention. Thus, the actual clock-time of melatonin administration also changes during the course of melatonin treatment using the methods of this invention. The time of endogenous melatonin onset, termed the dim light melatonin onset (DLMO) time, will vary in each individual human; however, the DLMO occurs at about 9 o""clock PM [circadian time (CT) 14] for most diurnal humans. Since the actual times of exogenous melatonin administration as provided by the methods of the instant invention are dependent on the time of an individual human""s dim light melatonin onset (DLMO) time (which will vary for each individual), circadian time will be used to most effectively represent all times discussed in this specification.
The present invention is based on the melatonin phase-response curve (PRC; see U.S. Pat. No. 5,242,941 and Example 2 below). The human melatonin PRC, shown in FIG. 1, indicates the presence of a time interval for each individual during which administration of exogenous melatonin results in clear and unequivocal phase-advance responses. Within this interval, the time of administration of melatonin is related to the magnitude of the resulting phase advance shift of the PRC. The human melatonin PRC also indicates the presence of a time interval for each individual during which administration of exogenous melatonin results in clear and unequivocal phasedelay responses. Within this interval, the time of administration of melatonin is related to the magnitude of the resulting phase delay shift of the PRC. The present invention directs the administration of melatonin to achieve phase advances between about CT 3 to about CT 18, and to achieve a phase delay between about CT 12 to about CT 6. The predicted phase advance or phase delay is more likely if the melatonin administration time occurs within these two intervals, respectively. The methods of the invention also take into account the additional fact that the zones for phase advance and phase delay overlap (i.e., between about CT 3 and CT 6 and also between about CT 12 and CT 19), as shown in FIG. 1.
The invention also relies on the identification of more precise intervals of melatonin administration times wherein the intervals of phase advance and phase delay responses do not overlap. For a phase advance, this unequivocal melatonin administration interval ranges from about CT 7 to about CT 11. For a phase delay, the melatonin administration interval is from about CT 20 to about CT 2.
The methods of the present invention thus provide for the administration of exogenous melatonin to effect a phase advance or a phase delay in the endogenous melatonin PRC. Preferred times of melatonin administration to effect a phase advance are about CT 3 to about CT 18, more preferably about CT 7 to about CT 11, most preferably about CT 7 to about CT 8. Preferred times of melatonin administration to effect a phase delay are about CT 12 to about CT 6, more preferably about CT 20 to about CT 2, and most preferably at about CT 0.
It will be understood by those with skill in this art that the methods of this invention thus prescribe exogenous melatonin administration times which will change relative to clock time during the course of exogenous melatonin treatment to effect a circadian rhythm phase shift. One novel and important aspect of the instant invention is that exogenous melatonin administration times are predicted relative to an internal circadian rhythm marker, the DLMO time, rather than external markers such as clock time (e.g., xe2x80x9cdestination bedtimexe2x80x9d). This aspect enables the instant invention to provide methods for achieving circadian rhythm phase-shifting effects that result in the effective treatment of a variety of circadian rhythm phase disturbances. In preferred embodiments, such circadian rhythm phase disturbances include jet lag, winter depression and shift-work and other human activity schedule-related disorders and de-synchronies with external zeitgebers.
Also contemplated as components of the methods of the instant invention are embodiments wherein melatonin administration is accompanied, either at administration times coincident with melatonin administration times or at appropriate times other than melatonin administration times, by exposure of a human to bright light, either artificial or naturally-occurring, or by limiting such exposure, that is, by prescribing the use of dark or red-colored goggles or other means to prevent a human from exposure to a light stimulus. Appropriate combinations of exogenous melatonin administration, dim light or bright light treatments are provided by this invention, as described more fully below.
Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.